Significant Adverse Risk Factor Research Articles

Effect of donor age on adult unrelated donor haemopoietic cell transplant outcome: the Australian experience.

Results have been varied regarding the effect of donor age on the outcome of unrelated donor haemopoietic cell transplantation (HCT). To determine the influence of donor age on adult unrelated donor HCT outcome in Australia. Patients were included in the study if they were aged 16 years or above and underwent first allogeneic unrelated donor HCT in Australia for the indications of acute lymphoblastic leukaemia (ALL), acute myelogenous leukaemia (AML), chronic myelogenous leukaemia (CML) or myelodysplastic syndromes (MDS) between the years of 2001 and 2014 inclusive. The main outcome measure was overall survival (OS), which was tested against independent variables using univariate Kaplan-Meier methods and multivariate Cox regression. A total of 1158 unrelated donor HCT were represented in the data. Cumulative incidences of engraftment, transplant related mortality (TRM), acute graft-versus-host disease (GvHD), chronic GvHD and relapse were not significantly affected by donor age. OS probability at 5 years post-transplant was 48.3%. In multivariate analysis of OS, year of transplant 2001-2007, recipient age 40 years or greater, poor risk disease, human leukocyte antigen (HLA) match less than 6/6 and poor performance status at transplant (Karnofsky scale) were independently significant adverse OS risk factors. Donor age was not a significant risk factor for OS in univariate or multivariate analysis. The conclusion from this study was that donor age (up to 59 years) did not influence post-transplant outcome among adult unrelated donor HCT performed in Australia for haematologic malignancies.

Is Performance of Routine Central Compartment Neck Dissection in cN0 Papillary Thyroid Cancers Really Useful? 10-Year Prospective Observational Study.

Central compartment nodes of neck are the first echelon nodes in papillary thyroid cancers (PTC). This study analyses the adverse parameters associated with central compartment nodal metastasis in cN0 PTC and also the usefulness of performing central compartment neck dissection routinely. A total of 236 patients with cNo PTC who underwent prophylactic central compartment neck dissection, from January 2008 to June 2017 in the Department of Oncology, Madurai Medical College, were included in study. Analysis of various adverse factors associated with central compartment nodal metastasis was made. Patients (46.18%) had metastatic nodes in the central compartment. Incidence of nodal metastasis increased with tumour size, capsular invasion, extrathyroidal extension, tracheal invasion and pulmonary metastasis. More than 50% patients did not have any of the statistically significant known adverse risk factors except for age and sex. Routine central compartment neck dissection has therapeutic value in PTC even in absence of known adverse factors and can be recommended in cases of clinically negative nodes. A meticulous dissection in experienced hands carries less complication rates as with thyroidectomy alone. In a resource limited country like ours, where the cost of re-surgery and radioiodine scans are high, a meticulous initial surgery incorporating central compartment neck dissection would really mean a difference.

Gemtuzumab Ozogamicin (GO) In Children With De Novo Acute Myeloid Leukemia (AML) Improves Event-Free Survival (EFS) By Reducing Relapse Risk – Results From The Randomized Phase III Children's Oncology Group (COG) Trial, AAML0531

▪ BackgroundEscalation of treatment intensity for childhood acute myeloid leukemia has improved EFS but with excessive toxicity and toxic mortality (TM), compelling a search for more targeted less toxic alternatives. ObjectiveTo determine if the addition of GO to standard chemotherapy improves EFS in pediatric AML. MethodsPatients < 30 years of age were randomly assigned to receive standard therapy alone (noGO) or to receive two doses of GO 3 mg/m2/dose on day 6 of Induction I (IndI) and on day 7 of Intensification II (IntII) in a 5 cycle chemotherapy backbone previously piloted by COG (Cooper et al, Cancer 2012). Use of stem cell transplant (SCT) was stratified by overall risk group assignment (based on cytogenetics, FLT3-ITD high allelic ratio (HAR), and IndI response) in which high risk patients were allocated to best allogeneic donor SCT after Int I, low risk (LR) patients received chemotherapy only, and intermediate risk (IR) were assigned to SCT if there was a matched family donor (MFD). ResultsBetween 2006-2010, 1022 of 1070 enrolled non-DS pts were eligible for analysis; characteristics are presented in Table 1. Median follow-up was 3.6 (range 0-6.4) years for those alive.Protocol therapy was well tolerated with a TM of 2% in induction and 5% overall with no difference by study arm. VOD was observed in 3% (severe in 0.6%) with no difference by study arm. From time of enrollment, GO was significantly associated with better overall EFS (hazard ratio (HzR) 0.83 (95% CI: 0.7-0.99; p=.04) and relapse-free survival (HzR 0.74 (0.6-0.93; p=.01)) whereas OS was not significantly improved (HzR 0.91 (0.74-1.13)). At 3 yr, noGO v GO EFS was 47 v 53%, p=.05 and OS was 65 v 69%, p=.18. In multivariate analyses, GO was significantly associated with improved EFS than standard therapy after adjustment for significant adverse risk factors: age <2yr, initial WBC>100,000x109/L, and black race. GO was not associated with significantly better induction complete remission (CR) when compared to standard therapy (88% v 85%; p=NS). Table 2 illustrates the overall results by randomized arm and by overall risk group from time of CR showing a consistent reduction in relapse risk in all risk groups. Further risk group analysis found several unique results. In the LR group, relapse rates (RR) trended lower in the GO arm but the benefit was reduced by TM during Int 2 & 3 that was significantly worse in the GO arm (3 v 10%, p=.02). In the IR group, EFS, RR, and OS trended towards improvement with GO. However when pts were censored at the time of SCT (as treated), the outcomes were not significantly different between arms (log-rank p=.14 EFS and p=.81 OS). Table 1 shows an imbalance for SCT received in assigned IR pts with fewer actually receiving SCT in the noGO arm. As such, Table 2 shows outcomes by intent-to-treat for IR pts with MFD censored and by as treated for IR pts receiving MFD SCT. Noteworthy in the IR group alone who did receive a SCT, GO arm pts had a significantly better DFS than the noGO arm (intent to treat: p=.022; as treated: p=.044). However, for the IR pts randomized to the noGO arm, SCT failed to provide benefit. For HR pts achieving CR they as well trended towards better survival & RR in the GO arm. ConclusionGO improves EFS in children, adolescents and young adults with AML by reducing the risk of relapse among those achieving remission. Disclosures:No relevant conflicts of interest to declare.

The assessment of risk factors for long-term survival outcome in ypN0 patients with rectal cancer after neoadjuvant therapy and radical anterior resection

BackgroundThe main negative prognostic factors in patients with rectal cancer after radical treatment include regional lymph node involvement, lymphovascular invasion, and perineural invasion. However, some patients still develop cancer recurrence despite the absence of the above risk factors.The aim of the study was to assess clinicopathological factors influencing long-term oncologic outcomes in ypN0M0 rectal cancer patients after neoadjuvant therapy and radical anterior resection.MethodsA retrospective survival analysis was performed on a group of 195 patients. We assessed clinicopathological factors which included tumor regression grade, number of lymph nodes in the specimen, Charlson comorbidity index (CCI), and colorectal anastomotic leakage (AL).ResultsIn the univariate analysis, AL and CCI > 3 had a significant negative impact on disease-free survival (DFS), disease-specific survival (DSS), and overall survival (OS). After the division of ALs into early and late ALs, it was found that only patients with late ALs had a significantly worse survival. The multivariate Cox regression analysis showed that CCI > 3 was a significant adverse risk factor for DFS (HR 5.78, 95% CI 2.15–15.51, p < 0.001), DSS (HR 7.25, 95% CI 2.25–23.39, p < 0.001), and OS (HR 3.9, 95% CI 1.72–8.85, p = 0.001). Similarly, late ALs had a significant negative impact on the risk of DFS (HR 5.05, 95% CI 1.97–12.93, p < 0.001), DSS (HR 10.84, 95% CI 3.44–34.18, p < 0.001), and OS (HR 4.3, 95% CI 1.94–9.53, p < 0.001).ConclusionsLate AL and CCI > 3 are the factors that may have an impact on long-term oncologic outcomes. The impact of lymph node yield on understaging was not demonstrated.

Hypodiploidy With Less Than 45 Chromosomes Confers Adverse Risk in Childhood Acute Lymphoblastic Leukemia: A Report From the Children's Cancer Group

AbstractWe have determined the prognostic significance of hypodiploidy (<46 chromosomes) in a large cohort of children with acute lymphoblastic leukemia (ALL) treated by the Children's Cancer Group. Among 1,880 patients, 110 (5.8%) had hypodiploid karyotypes: 87 had 45 chromosomes, 15 had 33 to 44 chromosomes, none had 29 to 32 chromosomes, and 8 had 24 to 28 chromosomes (near-haploidy). Six-year event-free survival (EFS) estimates for patients with 45 chromosomes, 33 to 44 chromosomes, or 24 to 28 chromosomes were 65% (standard deviation [SD], 8%), 40% (SD, 18%), and 25% (SD, 22%), respectively (log rank, P = .002; test for trend, P = .0009). The combined hypodiploid group had worse outcome than nonhypodiploid patients, with 6-year EFS of 58% (SD, 7%) and 76% (SD, 2%), respectively (P < .0001). EFS for the subgroup with 45 chromosomes was similar to that of patients with pseudodiploidy (P = .43) or 47 to 50 chromosomes (P = .76). None of the patients with 24 to 28 chromosomes had a t(4;11), a t(9;22), or a t(1;19), and most received highly intensive therapy. The adverse risk associated with 33 to 44 and 24 to 28 chromosomes remained significant in multivariate analyses adjusted for important risk factors including age, white blood cell count, and Philadelphia chromosome status. Thus, hypodiploidy with less than 45 chromosomes, particularly 24 to 28 chromosomes, is a significant adverse risk factor despite treatment with contemporary intensive therapies.

Risk factors of local recurrence after surgery in extraabdominal desmoid-type fibromatosis: A multicenter study in Japan.

This study was undertaken to clarify the risk factors, including the mutation status of CTNNB1, for the local recurrence after surgery of the rare disease desmoid‐type fibromatosis. It was designed as a multiinstitutional joint research project with 7 major centers in Japan participating. The committee members of 7 major medical centers specializing in bone and soft tissue tumors formed this study group to develop clinical care guidelines. Of 196 cases with specimens and medical records collected from the 7 institutions, 88 surgically treated ones were analyzed regarding clinicopathologic prognostic factors including CTNNB1 mutation status. Excluding R2 cases (n = 3), 5‐year local recurrence‐free survival (LRFS) was 52.9%. No case had received pre‐ or postoperative radiotherapy. Univariate analysis revealed that extremity location (P < .001) and larger size (8 cm or more, P = .036) were significant adverse risk factors for LRFS. Multivariate analysis indicated that extremity location (P < .001) was a significantly adverse factor in addition to recurrent tumor (P = .041), S45F mutation (P = .028), and R1 surgical margin (P = .039). Preoperative drug treatment, including nonsteroidal antiinflammatory drugs, did not reduce the incidence of local recurrence (P = .199). This is the first study to analyze the factors correlating with outcomes of surgical treatment, including CTNNB1 mutation status, in a relatively large number of cases from an Asian country. Tumor location was found to be the most influential prognostic factor for local recurrence, similar to the results from Europe and North America. The development of more sensitive method(s) for determination of CTNNB1 mutation is a priority for future study.

Correlation Between MYCN Gene Status and MYCN Protein Expression in Neuroblastoma: A Pilot Study To Propose the Use of MYCN Immunohistochemistry in Limited-Resource Areas

PURPOSEThe most significant adverse risk factor for neuroblastoma (NB) is MYCN gene amplification, which strongly associates with high-risk disease. Fluorescent in situ hybridization (FISH) is considered the best method to evaluate MYCN gene status. However, it requires a laboratory that can perform highly complex testing, specialized personnel, and costly reagents. Herein, we aimed to investigate the feasibility of using immunohistochemistry (IHC) to detect MYCN protein expression in lieu of FISH, a strategy potentially useful in areas with limited resources.METHODSA pilot cohort of 78 patients with NB, including 34 of Middle Eastern descent (MED) who had a higher prevalence of MYCN gene amplification (44.11%) and 44 of North American descent (NAD), nine (20.45%) of whom had MYCN amplification, was evaluated with IHC for MYCN protein. Correlations of FISH results and protein expression are presented.RESULTSA positive correlation between MYCN gene amplification and protein expression by IHC was seen in 22 (91.66%) of the 24 MYCN-amplified NB cases—14 (93.33%) of 15 patients of MED and eight (88.88%) of nine patients of NAD. Agreement between negative FISH and negative IHC results was noted in 18 (94.73%) patients of MED and 34 (97.14%) patients of NAD. Two cases had weak protein expression but no gene amplification (MED: n = 1; 5.0%; NAD: n = 1; 2.9%).CONCLUSIONAn excellent overall correlation between MYCN gene status by FISH and MYCN protein expression by IHC was confirmed. MYCN IHC in NB with reflexing to FISH in equivocal cases is potentially useful in a limited-resource setting. Evaluation of effectiveness using a larger cohort and optimization to perform MYCN IHC manually is needed.

SU132CANNABIS USE AND SCHIZOPHRENIA: CAN GENETICS TELL IF IS IT ``THE CHICKEN OR THE EGG''?

To study the risk factors for radiation-induced lung toxicity (RILT) after stereotactic body radiation therapy (SBRT) of the thorax.Published studies on lung toxicity in patients with early-stage non–small cell lung cancer (NSCLC) or metastatic lung tumors treated with SBRT were pooled and analyzed. The primary endpoint was RILT, including pneumonitis and fibrosis. Data of RILT and risk factors were extracted from each study, and rates of grade 2 to 5 (G2+) and grade 3 to 5 (G3+) RILT were computed. Patient, tumor, and dosimetric factors were analyzed for their correlation with RILT.Eighty-eight studies (7752 patients) that reported RILT incidence were eligible. The pooled rates of G2+ and G3+ RILT from all 88 studies were 9.1% (95% confidence interval [CI]: 7.15-11.4) and 1.8% (95% CI: 1.3-2.5), respectively. The median of median tumor sizes was 2.3 (range, 1.4-4.1) cm. Among the factors analyzed, older patient age (P=.044) and larger tumor size (the greatest diameter) were significantly correlated with higher rates of G2+ (P=.049) and G3+ RILT (P=.001). Patients with stage IA versus stage IB NSCLC had significantly lower risks of G2+ RILT (8.3% vs 17.1%, odds ratio = 0.43, 95% CI: 0.29-0.64, P<.0001). Among studies that provided detailed dosimetric data, the pooled analysis demonstrated a significantly higher mean lung dose (MLD) (P=.027) and V20 (P=.019) in patients with G2+ RILT than in those with grade 0 to 1 RILT.The overall rate of RILT is relatively low after thoracic SBRT. Older age and larger tumor size are significant adverse risk factors for RILT. Lung dosimetry, specifically lung V20 and MLD, also significantly affect RILT risk.

Down’s Syndrome ‑ An Independent Risk Factor of Outcomes in Isolated Congenital Duodenal Atresia

Introduction: There is no consensus in the available literature whether the coexistence of Down’s syndrome has adverse effect on the outcomes of neonates born with congenital duodenal atresia.Materials and Methods: A total of 29 neonates with congenital duodenal atresia were retrospectively studied for demographic details, sepsis parameters at admission, management, morbidity, and mortality. The neonates who were prematureResults: The sepsis parameters such as total leukocyte counts, erythrocyte sedimentation rate, serum procalcitonin levels, and serum C‑reactive protein levels were significantly increased, and the platelets were significantly decreased at admission in Group B subjects, as compared to Group A subjects. There were no complications noted in Group A, while Group B had significant morbidity. The neonates with congenital duodenal atresia with Down’s syndrome had 3.27 times more relative risk of mortality than those without Down’s syndrome. Down’s syndrome appears to be an independent risk factor for mortality in isolated congenital duodenal atresia with attributable risk of 37.8%.Conclusion: The presence of Down’s syndrome is a significant independent adverse risk factor of outcomes in isolated congenital duodenal atresia.

Simple Factors Associated With Radiation-Induced Lung Toxicity After Stereotactic Body Radiation Therapy of the Thorax: A Pooled Analysis of 88 Studies

To study the risk factors for radiation-induced lung toxicity (RILT) after stereotactic body radiation therapy (SBRT) of the thorax. Published studies on lung toxicity in patients with early-stage non-small cell lung cancer (NSCLC) or metastatic lung tumors treated with SBRT were pooled and analyzed. The primary endpoint was RILT, including pneumonitis and fibrosis. Data of RILT and risk factors were extracted from each study, and rates of grade 2 to 5 (G2+) and grade 3 to 5 (G3+) RILT were computed. Patient, tumor, and dosimetric factors were analyzed for their correlation with RILT. Eighty-eight studies (7752 patients) that reported RILT incidence were eligible. The pooled rates of G2+ and G3+ RILT from all 88 studies were 9.1% (95% confidence interval [CI]: 7.15-11.4) and 1.8% (95% CI: 1.3-2.5), respectively. The median of median tumor sizes was 2.3 (range, 1.4-4.1) cm. Among the factors analyzed, older patient age (P=.044) and larger tumor size (the greatest diameter) were significantly correlated with higher rates of G2+ (P=.049) and G3+ RILT (P=.001). Patients with stage IA versus stage IB NSCLC had significantly lower risks of G2+ RILT (8.3% vs 17.1%, odds ratio=0.43, 95% CI: 0.29-0.64, P<.0001). Among studies that provided detailed dosimetric data, the pooled analysis demonstrated a significantly higher mean lung dose (MLD) (P=.027) and V20 (P=.019) in patients with G2+ RILT than in those with grade 0 to 1 RILT. The overall rate of RILT is relatively low after thoracic SBRT. Older age and larger tumor size are significant adverse risk factors for RILT. Lung dosimetry, specifically lung V20 and MLD, also significantly affect RILT risk.

Male gender is an adverse risk factor only in young patients with diffuse large B-cell lymphoma – a Swedish population-based study

Background. Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of B-cell lymphomas. Five clinical adverse risk factors are merged into the International Prognostic Index (IPI), which is the major tool for prognostication. In contrast to Hodgkin's lymphoma, gender is not considered as an adverse risk factor for DLBCL patients. As we clinically had observed a very good survival rate in young female patients we hypothesised that there was a gender difference in survival due to the hormonal status of the patient.Material and methods. We conducted a registry-based retrospective cohort study of all Swedish DLBCL patients diagnosed between 2000 and 2013, to evaluate the impact of gender for survival from DLBCL.Results. In total, 7166 patients were included for further analysis. No survival difference was found between the genders when the entire population was analysed. However, analysis of 880 young patients of pre-menopausal age (i.e. 52 years) revealed that women had a longer survival compared to men of the same age group (p = 0.007). This was not found for patients older than menopausal age. In a relative survival multifactorial model adjusted for stage, ECOG performance status, serum lactate dehydrogenase and two or more extranodal sites, male gender was found to be an adverse risk factor for patients younger than 52 years (RR 1.51, 95% CI 1.14–1.88), but not for older patients (RR 0.99, 95% CI 0.89–1.10).Conclusion. This is one of the largest population-based studies of DLBCL presented to date. Most interestingly, we found male gender to be a significant adverse risk factor compared to fertile women whereas we found no survival differences between genders in the older sub-population.

The impact of age on survival of diffuse large B-cell lymphoma – a population-based study

Background. For Diffuse large B-cell lymphoma (DLBCL), the International Prognostic Index is the major tool for prognostication and considers an age above 60 years as a risk factor. However, there are several indications that increasing age is associated with more biological complexity, resulting in differences in DLBCL biology depending on age.Methods. We conducted a registry-based retrospective cohort study of all Swedish DLBCL patients diagnosed 2000–2013, to evaluate the importance of age at diagnosis for survival of DLBCL patients.Results. In total, 7166 patients were included for further analysis. Survival declined for every 10-year age group and every age group above the age of 39 had a statistically decreased survival compared to the reference group of 20–29 years. In an analysis of relative survival, and in a multifactorial model adjusted for stage, ECOG performance status, serum lactate dehydrogenase and involvement of extranodal sites, each age group above age 39 had a significantly higher risk ratio (p = 0.01) compared to the reference group.Conclusion. This is one of the largest population-based studies of DLBCL published to date. In this study, age persisted as a significant adverse risk factor for patients as young as 40 years, even after adjustment for other risk factors.

The Impact of Different DNMT3A Mutations on Outcome in Younger Adults with Acute Myeloid Leukemia

▪DNMT3A mutations (DNMT3AMUT) are recurrent in AML. They predominate in patients with intermediate-risk (IR) cytogenetics and are often co-incident with FLT3ITD and NPM1MUT. Their prognostic impact is unclear. Most reports suggest they are associated with a worse outcome, but a large study including 1060 younger adult IR patients found that DNMT3AMUT had no significant impact on survival endpoints. Variable results have also been reported for different FLT3/NPM1 subgroups. Missense mutations at R882 in exon 23 occur in ≈65% of patients, but other missense and truncation mutations occur throughout the gene, mainly in exons 13-23. There is limited information on the prognostic impact of the different mutations, although they may have differing functional consequences. We therefore screened exons 13-23 in DNA samples from 914 younger adult AML patients (median age 43 years) with IR cytogenetics treated on UK MRC trials and evaluated outcome according to type of DNMT3Amutation.Overall, 278 mutations were detected in 272 (30%) patients; 175 (64%) had R882 missense mutations, 59 (22%) other missense mutations, 35 (13%) truncations or in-frame deletions; 3 (1%) had 2 mutations of differing types. Median R882 mutant level in 172 mutated cases was 47% (range 15-85%), consistent with a heterozygous mutation in most cells. Patients with DNMT3AMUT were significantly older than those with DNMT3A wild-type (DNMT3AWT) (P<.0001), more likely to be female (P=.004), have a higher presenting WBC (P<.0001), and a normal rather than abnormal karyotype (P<.0001). The presence of DNMT3AMUT positively correlated with FLT3ITD (P=.0003) and NPM1MUT (P<.0001) and negatively correlated with CEBPAMUT (P<.0001). Patients with R882 mutations had significantly higher WBC (P=.005) and correlation with NPM1MUT (P=.01) than non-R882 mutated patients; non-R882 missense mutated patients had higher WBC (P=.05) and non-significant higher co-incidence with FLT3ITD than those with truncations.Presence of DNMT3AMUT was associated with a poorer prognosis, but this difference was only seen if the results were analyzed separately according to NPM1 genotype, where DNMT3AMUT was associated with higher cumulative incidence of relapse (CIR) than DNMT3AWT in cases with NPM1MUT (49% vs 40%, P=.01) and NPM1WT (61% vs 58%, P=.5) genotype. Similarly, DNMT3AMUT patients had worse overall survival (OS) than DNMT3AWT patients with NPM1MUT (38% vs 50%, P=.008) and NPM1WT (15% vs 25%, P=.09) genotype. This statistical anomaly is an example of Simpson’s paradox. It results from the strong co-incidence of DNMT3A and NPM1 mutations with opposing prognostic associations that mask the effect seen separately when the groups are combined. Although the differences were smaller for NPM1WT cases, tests for heterogeneity showed that the impact of a DNMT3A mutation did not differ between NPM1MUT and NPM1WT for either CIR or OS, nor between the 4 genotypes defined by the combination of NPM1 and FLT3ITD genotypes. In multivariable analysis including age, WBC, NPM1 and FLT3ITD, DNMT3AMUT was a significant adverse risk factor for CIR (HR=1.27, CI=1.01-1.61; P=.04), and showed a trend for being adverse for OS (HR=1.19, CI=.98-1.45; P=.08).When outcome was considered according to the type of mutation (R882, other missense or truncations), for the NPM1MUT genotype cases CIR was highest in R882 and other missense cases (51%, 50%) and truncation cases were similar to DNMT3AWT (35%, 40%). For NPM1WT, CIR was highest in R882 cases (76%), similar in other missense and DNMT3AWT cases (55%, 58%) and lowest in truncation cases (40%). Consistent with this data, for NPM1MUT genotype, OS was lowest in R882 and other missense cases (35%, 38%), better in DNMT3AWT (50%) and highest in truncation cases (57%). For NPM1WT, OS was lowest in R882 cases (11%), and similar in DNMT3AWT, other missense and truncation cases (25%, 21%, 18% respectively).These data suggest that screening cannot be limited to the hotspot R882 mutations and that cases with missense mutations should be treated as poor risk, including those patients currently considered as favorable risk such as NPM1MUTFLT3WT. Conversely, truncation mutations have a different functional impact from missense mutations, more likely to result in haploinsufficiency than a dominant-negative effect, and these cases should be considered as equivalent to DNMT3AWT for prognostication and selection of therapy in 1st remission. DisclosuresNo relevant conflicts of interest to declare.

Sex-specific associations of cardiovascular risk factors with carotid stiffness – Results from the SAPALDIA Cohort Study

ObjectiveManifestation of cardiovascular disease (CVD) occurs with clear sex differences. Carotid stiffness (CS) parameters are increasingly used for CVD risk assessment but the sex-specific association with CVD risk factors as well as association patterns between CS parameters are largely unknown, which we investigated in SAPALDIA population-based cohort participants. MethodsRisk factors of 2545 participants without clinically manifest disease were evaluated in 2001–2003 and different CS parameters were assessed in carotid ultrasound scans in 2010–2011. Stratified and non-stratified mixed linear models and multivariate regression analyses were used to examine sex-specific associations, differences and association patterns of single risk factors and CS parameters. ResultsHDL cholesterol was the only significant protective determinant of reduced CS for both sexes (ranges of CS parameters: −3.7; −0.8% of changes in geometric mean per 1SD of the risk factor on an inverted scale) and significant adverse risk factors were BMI (−0.5; 4.7%), systolic (−1.23; 4.7%) and diastolic blood pressure (1.4; 4.4%), heart rate (2.7; 7.9%), C-reactive protein (0.6; 3.3%) and smoking (−2.82; 1%), all p-values of multivariate analyses were <0.01. Sex differences with stiffer CS parameters in men were observed for increased heart rate (p = 0.001) and LDL cholesterol (p < 0.001) and in women for triglyceride (p < 0.003). Similar association patterns were found for most CS parameters. ConclusionSex-specific associations of cardiovascular risk factors may reflect a sex-specific burden of atherosclerotic risk factors and similar association patterns across different CS parameters within men and women may allow the use of CS parameters in an exchangeable manner.

Fludarabine Melphalan reduced-intensity conditioning allotransplanation provides similar disease control in lymphoid and myeloid malignancies: analysis of 344 patients

This was an Australasian Bone Marrow Transplant Recipient Registry (ABMTRR)-based retrospective study assessing the outcome of Fludarabine Melphalan (FluMel) reduced-intensity conditioning between 1998 and 2008. Median follow-up was 3.4 years. There were 344 patients with a median age of 54 years (18-68). In all, 234 patients had myeloid malignancies, with AML (n=166) being the commonest indication. There were 110 lymphoid patients with non-hodgkins lymphoma (NHL) (n=64) the main indication. TRM at day 100 was 14% with no significant difference between the groups. OS and disease-free survival (DFS) were similar between myeloid and lymphoid patients (57 and 50% at 3 years, respectively). There was no difference in cumulative incidence of relapse or GVHD between groups. Multivariate analysis revealed four significant adverse risk factors for DFS: donor other than HLA-identical sibling donor, not in remission at transplant, previous autologous transplant and recipient CMV positive. Chronic GVHD was associated with improved DFS in multivariate analysis predominantly due to a marked reduction in relapse (HR:0.44, P=0.003). This study confirms that FluMel provides durable and equivalent remissions in both myeloid and lymphoid malignancies. Disease stage and chronic GVHD remain important determinants of outcome for FluMel allografting.

Providing Personalized Prognostic Information for Adult Leukemia Survivors

Prediction of subsequent leukemia-free survival (LFS) and chronic graft-versus-host disease (GVHD) in adults with acute leukemia who survived at least 1 year after allogeneic hematopoietic cell transplantation is difficult. We analyzed 3339 patients with acute myeloid leukemia and 1434 patients with acute lymphoblastic leukemia who received myeloablative conditioning and related or unrelated stem cells from 1990 to 2005. Most clinical factors predictive of LFS in 1-year survivors were no longer significant after 2 or more years. For acute myeloid leukemia, only disease status (beyond first complete remission) remained a significant adverse risk factor for LFS 2 or more years after transplantation. For lymphoblastic leukemia, only extensive chronic GVHD remained a significant adverse predictor of LFS in the second and subsequent years. For patients surviving for 1 year without disease relapse or extensive chronic GVHD, the risk of developing extensive chronic GVHD in the next year was 4% if no risk factors were present and higher if noncyclosporine-based GVHD prophylaxis, an HLA-mismatched donor, or peripheral blood stem cells were used. Estimates for subsequent LFS and extensive chronic GVHD can be derived for individual patients or populations using an online calculator (http://www.cibmtr.org/LeukemiaCalculators). This prognostic information is more relevant for survivors than estimates provided before transplantation.

Risk Factor Analysis for Second-Stage Palliation of Single Ventricle Anatomy

Single ventricle hearts can be surgically palliated by a series of operations culminating in the Fontan procedure, which establishes a total cavopulmonary connection. The second-stage procedure creates a physiologic connection between the superior vena cava and the pulmonary artery. From 1998 to 2010, 557 patients with single ventricle heart disease underwent second-stage surgical palliation. This cohort was retrospectively analyzed to assess patient outcome by a number of anatomic, physiologic, and procedural factors. The analysis excluded patients undergoing hybrid first-stage procedures. The median age at operation was 165 days (range, 59 days to 49 years). The most common anatomic subtypes were hypoplastic left heart syndrome (52%), tricuspid atresia (12%), unbalanced atrioventricular septal defect (10%), double inlet left ventricle (9%), or other (17%). Left ventricular hypoplasia was present in 70%. A hemi-Fontan procedure was done in 89%, and 11% received a bidirectional Glenn. Concomitant atrioventricular valve repair was necessary in 9%. Early mortality was 4.7%, and 5.9% died after discharge but before Fontan. No early or late deaths occurred in patients with tricuspid atresia and double inlet left ventricle. Multivariate analysis demonstrated ventricular dysfunction, atrioventricular valve regurgitation, and unbalanced atrioventricular septal defect were significant adverse risk factors for survival to Fontan. Second-stage palliation can be performed at low risk for patients with left ventricular dominance, but significant risk remains for patients with left ventricular hypoplasia and unbalanced atrioventricular septal defect. Atrioventricular valve insufficiency is a persistent problem that has not been neutralized by repair strategies.

A Unified Prognostic Model for Myelodysplastic Syndrome and Acute Myeloid Leukaemia Based on Flow Cytometric Blast Count

Abstract 1736The distinction between Acute Myeloid Leukaemia (AML) and Myelodysplastic Syndrome (MDS), together with its prognostic assessment, depends on the proportion of bone marrow blast cells. The International Prognostic Scoring System (IPSS) uses this value to predict survival in conjunction with cytogenetic and blood count parameters. Current practice in most centres is to count blast cells manually on stained smears and to assign patients to one of 4 bands (<5%, 6–10%,11-19% and >20%). This approach has two major disadvantages. Firstly, the evaluation of cellular morphology is subjective and the standard error of a manual count is sufficiently large that many patients cannot be assigned with reasonable accuracy to a category - which can critically impact on their care. Secondly, assigning patients into broad groups, instead of retaining blast cell count as a continuous variable, may be degrading important prognostic information.Modern flow cytometric techniques allow blast cells to be counted with high levels of accuracy. In this study we used a standard five colour assay including CD34, CD117, CD15, CD3, CD19 and physical characteristics to count bone marrow blast cells. Bone marrows from 271 patients with AML/MDS treated with curative intent (median age, 59 yrs; M: F,1.22) and 684 patients treated with supportive therapy (median age, 77 yrs; M: F,1: 1.8) were evaluated. Patients with acute promyelocytic leukaemia (APML), AML with t(8;21) or inv 16 were excluded. All patients were from a population-based cohort (www.hmrn.org), and all diagnostic studies were performed using standard protocols in a single laboratory. A prognostic model was constructed using age, flow cytometric blast cell count and gender. In non-intensively treated patients survival declined rapidly with blast counts up to 10% and then decreases much more slowly. Age had a minimal effect on survival under the age of 70, but prognosis declined rapidly in older patients. Male gender was a significant adverse risk factor (hazard ratio = 1.47). In contrast, patients who were treated intensively showed only a modest relationship between blast count and prognosis but a much more marked effect of age. Survival declined progressively from 20 years with the trend accelerating in those over 60 years. There was also a smaller effect of gender in those receiving intensive treatment (hazard ratio = 1.09). In MDS patients, a complex relationship between blast cell count, standard cytogenetic risk factors and the degree of cytopenia was observed.Using age and flow cytometric blast count as continuous variables, modelled using restricted cubic splines, together with gender enabled more accurate outcome prediction in patients with AML and MDS across the full range of blast counts. This is possible because of the much higher levels of accuracy of flow cytometry compared to manual counting methods. The main practical advantage of a unified prognostic model is that it allows the relative benefits of intensive and non-intensive treatment to be readily compared for an individual patient. The predictive power of this core model can be improved further by the inclusion of additional clinical and molecular data. MDS and most forms of AML are part of a continuous spectrum of disease. A more unified approach to classification avoiding arbitrary subdivision may improve clinical decision making in this complex group of patients. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Tumor Necrosis as a Prognostic Factor for Stage IA Non-Small Cell Lung Cancer

In stage IA non-small cell lung cancer (NSCLC), lobectomy and mediastinal lymph node dissection is considered the standard treatment. However, 20% to 30% of patients have cancer recurrences. The purpose of this study was to determine the patterns and risk factors for recurrence in patients with stage IA NSCLC. We retrospectively reviewed the medical records of 201 patients who had confirmed stage IA NSCLC by lobectomy and complete lymph node dissection. There were 131 male patients with a mean age of 60.68±9.26 years. The median follow-up period was 41.4 months. Recurrences were reported in 16 patients. One hundred fourteen and 87 patients were T1a (≤2 cm) and T1b (>2 cm to ≤3 cm), respectively. The pathologic results were as follows: adenocarcinomas and bronchioloalveolar carcinomas (n=134); squamous cell carcinomas (n=57); and other diagnoses (n=10). Tumor necrosis and lymphatic invasion were significant adverse risk factors for recurrence based on univariate analysis. Multivariate analysis showed that tumor necrosis was the only significant risk factor to predict cancer recurrence (hazard ratio, 4.336; p=0.032). The 5-year overall survival was 94.8% for necrosis-negative patients and 86.2% for necrosis-positive patients (p=0.04). The 5-year disease-free survival was 92.1% for necrosis-negative patients and 78.9% for necrosis-positive patients (p=0.016). Tumor necrosis was shown to be an adverse risk factor for survival and recurrence in patients with stage IA NSCLC. Thus, close observation and individualized adjuvant therapy might be helpful for patients with stage IA NSCLC with tumor necrosis.

High-dose CHOP plus etoposide (MegaCHOEP) in T-cell lymphoma: a comparative analysis of patients treated within trials of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL)

BackgroundT-cell lymphomas (T-NHL) generally carry a poor prognosis. High-dose therapy (HDT) and autologous stem cell transplantation (ASCT) are increasingly used to treat younger patients. Design and methodsWe treated patients <61 years with high-risk aggressive lymphoma with four to six courses of dose-escalated CHOP plus etoposide (MegaCHOEP) necessitating repeated ASCT. Outcomes of patients with mature T-NHL (excluding anaplastic lymphoma kinase-positive anaplastic large cell lymphoma) and aggressive B-NHL were compared using multivariate Cox regression analysis. ResultsCompared with 84.4% of B-NHL patients, 66.7% of T-NHL patients were able to receive all treatments; the rates of progressive disease were 27.3% in T-NHL and 16.3% in B-NHL patients. At 3 years, event-free survival (EFS) and overall survival were significantly worse for T-NHL [25.9% confidence interval (CI) 10.4% to 41.4% and 44.5% CI 26.5% to 62.5%) than for B-NHL patients (60.1% CI 52.1% to 68.1%; P < 0.001 and 63.4% CI 55.4% to 71.4%; P = 0.016). In multivariate analysis, T-NHL was a strongly significant adverse risk factor for EFS (relative risk 2.2, P=0.001). ConclusionsMegaCHOEP for T-NHL patients was no better than other high-dose regimens and was unable to address the major problems of HDT/ASCT: neither early progressions nor early relapses were reduced. This study sheds some doubt on expectations that HDT/ASCT will significantly improve outcomes for patients with T-NHL.